Pathogenic fungi occur worldwide and can cause diseases in humans, animals and plants. Fungal infections in humans range from superficial, e.g., skin surface to deeply invasive type or disseminated infection. Some of such infections especially those that are disseminated are fatal. Thus, fungal diseases can be divided into the life-threatening systemic infections, such as histoplasmosis, systemic candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, and cryptococcosis, and more common ones which are non-life-threatening, like dermatophyte (ringworm) infections, including tinea pedis (athlete's foot), tinea cruris (jock itch), candidiasis, and actinomycosis.
The life-threatening fungal infections are a growing problem not only for immunosuppressed or immunocompromised individuals but also in individuals with viral infections, such as cytomegalovirus (CMV), and influenza, for cancer patients receiving chemotherapy or radiotherapy, for transplant patients receiving antirejection agents, and for patients that have received toxic chemicals, metals and radiation exposure. Fungal opportunistic infections, such as candidiasis, cryptococcosis, and histoplasmosis, occur frequently in patients with AIDS. Among the opportunistic infections, fungal infections caused by Pneumocystis, Candida, Cryptococcus, or Histoplasma are very common and prevalence can be as high as 85% among HIV-infected individuals. The incidence of systemic fungal infections increased 600% in teaching hospitals and 220% in non-teaching hospitals during the 1980's. The most common clinical isolate is Candida albicans (comprising about 19% of all isolates). Nearly 40% of all deaths from hospital-acquired infections were due to fungi.
The treatment of fungal infections has lagged behind bacterial chemotherapy. There are substantially fewer antifungal drugs than antibacterial drugs. The majority of known antifungal agents fall into one of three main groups. The major group includes polyene derivatives, including amphotericin B and the structurally related compounds nystatin and pimaricin, which are only administered intravenously. These are broad-spectrum antifungals that bind to ergosterol, a component of fungal cell membranes, and thereby disrupt the membranes, leading to cell death. Amphotericin B is usually effective for systemic mycoses, but its administration is limited by toxic effects that include fever and kidney damage, and other accompanying side effects, such as anemia, low blood pressure, headache, nausea, vomiting and phlebitis. The unrelated antifungal agent flucytosine (5-fluorocytosine), an orally absorbed drug, is frequently used as an adjunct to amphotericin B treatment for some forms of candidiasis and cryptococcal meningitis. Its adverse effects include bone marrow depression with leukopenia and thrombocytopenia.
The second major group of antifungal agents includes azole derivatives which impair synthesis of ergosterol via lanosterol demethylase and lead to accumulation of metabolites that disrupt the function of fungal membrane-bound enzyme systems (e.g., cytochrome P450) and inhibit fungal growth. Significant inhibition of mammalian P450 results in important drug interactions. This group of agents includes ketoconazole, clotrimazole, miconazole, econazole, butoconazole, oxiconazole, sulconazole, terconazole, fluconazole and itraconazole. These agents may be administered to treat systemic mycoses. Ketoconazole, an orally administered imidazole, is used to treat nonmeningeal blastomycosis, histoplasmosis, coccidioidomycosis and paracoccidioidomycosis in non-immunocompromised patients, and is also useful for oral and esophageal candidiasis. Adverse effects include rare drug-induced hepatitis; ketoconazole is also contraindicated in pregnancy. Itraconazole appears to have fewer side effects than ketoconazole and is used for most of the same indications. Fluconazole also has fewer side effects than ketoconazole and is used for oral and esophageal candidiasis and cryptococcal meningitis. Miconazole is a parenteral imidazole with efficacy in coccidioidomycosis and several other mycoses, but has side effects including hyperlipidemia and hyponatremia.
The third major group of antifungal agents includes allylamnines-thiocarbamates, which are generally used to treat skin infections. This group includes tolnaftate and naftifine. Another antifungal agent is griseoflulvin, a fungistatic agent which is administered orally for fungal infections of skin, hair or nails that do not respond to topical treatment.
Limitations of current therapeutic options include: inadequate spectrum of activity, lack of efficacy due to growing resistance, poor safety profile, multiple drug interactions, inadequate pharmacokinetic profile, and excessive cost. Development of antifungal agents is a challenge because there are very few potential drug targets unique to fungi. Experts in fungal field agree that new drugs needs to be developed. Three novel azoles that offer improved potency and a wide spectrum of activity are in late-stage development: voriconazole, posaconazole, and ravuconazole. Another new class of agents, the candins—are a novel generation of cell-wall active semisynthetic 1,3 beta-glucan inhibitors—caspofungin, micafungin, and anidulafungin. There is also so-called Nyotran, a novel liposomal formulation of nystatin. In addition, a new class of protein synthesis inhibitors, the sordarins, are in preclinical development. Resistance to antifungals has become more apparent in recent years and may worsen with the increase in prophylatic therapy even with new drugs being developed.